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Harmer CJ, Bhagwagar Z, Cowen PJ, Goodwin GM. Acute administration of

citalopram facilitates memory consolidation in healthy volunteers.
Psychopharmacology (Berlin) 163: 106-110

Article  in  Psychopharmacology · September 2002

DOI: 10.1007/s00213-002-1151-x · Source: PubMed

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Psychopharmacology (2002) 163:106–110
DOI 10.1007/s00213-002-1151-x
ORIGINAL INVESTIGATION
Catherine J. Harmer · Zubin Bhagwagar ·
Phillip J. Cowen · Guy M. Goodwin
Acute administration of citalopram facilitates memory consolidation
in healthy volunteers
Received: 8 February 2002 / Accepted: 8 May 2002 / Published online: 29 June 2002
5 Springer-Verlag 2002
Abstract Objectives: Decreasing serotonergic neurotrans-
mission in humans has been found to impair memory
consolidation. Such effects may be relevant to the
memory deficits seen in major depression and the
cognitive actions of antidepressant drugs used to treat
them. However, the improvement in cognitive function
often found following successful pharmacological treat-
ment in depression may be confounded by symptom
improvement. Rationale: The present study assessed the
effects of an acute challenge with the selective seroto-
nergic re-uptake inhibitor citalopram in healthy (non-
depressed) females. Methods: Immediate and delayed
recall/recognition was assessed using the auditory verbal
learning test following 10 mg (intravenous) citalopram or
placebo in a double-blind between groups design.
Results: Immediate recall on the verbal memory test
was unaffected by citalopram administration. However,
volunteers receiving citalopram showed enhanced long-
term memory performance in terms of delayed recall and
recognition relative to those receiving placebo. Sustained
attention performance was also comparable in the two
groups of subjects suggesting that non-specific increases
in information processing are not responsible for this
effect. Conclusions: These results indicate that augmen-
tation of serotonergic neurotransmission is associated
with increased memory consolidation, which may be
relevant to its therapeutic and cognitive actions in acutely
depressed patients.
Keywords SSRI · Citalopram · Memory consolidation ·
Serotonin
C.J. Harmer ()) · Z. Bhagwagar · P.J. Cowen · G.M. Goodwin
Neurosciences Building, University Department of Psychiatry,
Warneford Hospital, Oxford OX3 7JX, UK
e-mail: catherine.harmer@psych.ox.ac.uk
Tel.: +44-1865-226492
Fax: +44-1865-251076
Introduction
Serotonergic circuits have long been held to play a role in
learning and memory processes. However, results from
animal studies have yielded inconsistent findings con-
cerning the direction of its effect (Altman and Normile
1988). While there is evidence that stimulation of
serotonin activity impairs, whereas blockade of its
activity enhances, learning and memory (see McEntee
and Crook 1991), the opposite findings have also been
reported (e.g. Bammer 1982; Flood and Cherkin 1987).
These inconsistencies may relate to interactions between
the type of memory assessed, dose and specificity of
agents used and the timing of the serotonergic manipu-
lations (Altman and Normile 1988).
In humans, decreasing serotonergic neurotransmission,
using the method of tryptophan depletion, has been
reported to decrease memory and learning (Park et al.
1994; Riedel et al. 1999; Schmitt et al. 2000). In
particular, long-term, as opposed to short-term, memory
appears to be primarily affected. In the study by Riedel et
al. (1999), immediate recall of verbal items was unaf-
fected by tryptophan depletion, but delayed recall and
recognition of these same items was significantly im-
paired. In a subsequent investigation, only tryptophan
depletion given prior to learning affected delayed recall.
Administration of the tryptophan-free drink 1 h after
presentation of a word list did not affect the storage or
retrieval of this verbal material (Schmitt et al. 2000). The
involvement of serotonin in memory does not appear to
be restricted to verbal material, as tryptophan depletion
has also been reported to impair performance in non-
verbal memory tasks, such as paired associate learning
and pattern recognition memory (Park et al. 1994;
Rubinsztein et al. 2001).
A role for serotonin in learning and memory may be
relevant to clinical conditions such as depression, Alz-
heimer’s disease and the symptoms associated with prior
ecstasy (MDMA) use. Major depressive disorder has been
associated with impaired recall both on immediate and
delayed measures (Austin et al. 1992; Brown et al. 1994),

and memory deficits are usually seen to improve follow-
ing recovery from the disorder with antidepressant
treatment (Peselow et al. 1991), particularly selective
serotonergic reuptake inhibitors (SSRIs) (Keegan et al.
1991; Bondareff et al. 2000). This improvement may be
related to direct actions of the antidepressant on memory
or may be a non-specific effect of symptom improvement.
Similarly, deficits in immediate and delayed memory
have been reported to occur in individuals with past
history of ecstasy use with associated abnormalities of
serotonergic functioning (e.g. Reneman et al. 2000,
2001).
The effects of increased, as opposed to decreased,
serotonin levels have not been investigated to the same
degree in humans. Such results may help confirm the role
of serotonin in memory processes and also provide a
possible mechanism for the cognitive effects of antide-
pressant treatment in major depression. The present study
therefore investigated the effects of an acute challenge
with the SSRI, citalopram, on verbal short and long-term
memory in non-depressed female subjects. Sustained
attention was also examined to assess whether more
global changes in information processing were found
following SSRI treatment. Based on the effects of
tryptophan depletion in humans, it was postulated that
citalopram would specifically facilitate long-term mem-
ory recall and recognition, without affecting immediate
recall and mood.
Materials and methods
Subjects
Twenty-four healthy female volunteers between the ages of 21 and
59 years took part in this study. Participants were screened to
exclude those with a current or previous history of psychiatric
disorder (assessed using semi-structured interview for DSM IV),
current medication (apart from the contraceptive pill), current or
previous substance use, or significant physical illness. All gave
their written consent to participate in this study, which was
approved by the local ethical committee. Volunteers were randomly
allocated to receive citalopram (10 mg, IV) or placebo in a double-
blind between groups design. These two groups were matched in
terms of age (mean age: 40.1€3.6 and 37.3€3.7 years, respectively)
and years of education (mean: 13.4€0.7; 14.6€0.7). All volunteers
were tested within the follicular phase of their menstrual cycle.
Auditory verbal learning test (AVLT)
The auditory verbal learning test assesses a number of different
components of learning, recall, and recognition (Rey 1964). In the
immediate recall phase, a 15-item word list was read to the subject
five times, and after each trial the subject was asked to repeat back
as many items as they could remember in any order. Immediate
recall on a distracter list was then assessed, providing a short delay
after which free recall of the original list was tested. Fifteen
minutes later, subjects were tested for long delay free recall,
followed by a recognition test, where they were asked to respond
with a “Yes” or “No” to each item on a list comprising the 15
targets plus 35 distractors. Data were analysed with respect to four
dependent variables: learning over trials 1–5, short-delay and long-
delay free recall (expressed as a percentage of performance on the
107
final learning trial), and recognition. Signal detection theory was
applied to the data from the recognition test to derive a measure of
accuracy corrected for the subject’s response tendency. The
proportion of correctly recognized words (cr) and the proportion
of falsely recognized (fr) constitute the non-parametric sensitivity
measure: A’=1–1/4(fr/cr+(1–cr)/(1–fr)).
Sustained attention
A measure of sustained attention was also given, adapted from a
test by Wesnes and Warburton (1984) and Sahakian et al. (1989). In
this task, digits between 1 and 9 were presented in the centre of the
screen at a rate of 200 per minute (pseudo-random order) for 7 min.
Subjects were asked to monitor the digits for any one of three
specified digit sequences (3–5–7, 2–4–6 or 4–6–8), which they
should respond to by pressing a button on a key pad. A practice
session was given initially, with target sequences appearing in red,
to familarise volunteers with the nature of the task. In the testing
phase all digits were given in black on a white screen. This task
yields three measures: speed of correct detections, number of
correct detections and responses made in the absence of appropriate
stimuli (false alarms). Signal detection analysis can also be applied
to these results, giving two independent measures of performance:
response sensitivity and response bias.
Subjective state
Subjective state was recorded using visual analogue scales for the
following variables: happiness, sadness, fear, disgust, anger,
alertness and anxiety. The Befindlichkeits scale (BFS: von Zerrsen
et al. 1974) was also given to provide an additional measure of
mood.
Procedure
Subjects attended the laboratory at midday, having fasted from
breakfast, and an IV cannula was inserted. After a 30-min rest
period subjects received infusion of either citalopram (10 mg, IV)
or placebo given over 30 min. The immediate recall part of the
AVLT was given 45 min after the end of the infusion, by which
time effects of citalopram on serotonin function have been reported
(Attenburrow et al. 2001). In between the distraction and delayed
recall, subjects were given the sustained attention task. Subjective
state was assessed at baseline and prior to the psychological testing.
Statistical analysis
Performance in these tasks was analysed using two-way split-plot
analysis of variance (ANOVA), with group and learning trial as
factors (for immediate and delayed recall). Significant main effects
were completed using simple main effect analyses. Recognition
memory was analysed using one-way ANOVA.
Results
Immediate recall
Recall of the 15-item word list improved over the five
repetitions in both groups of subjects [Fig. 1: main effect
of trial: F(4,88)=108.7, P<0.001]. However, there was no
effect of group or group by trial interaction in this
analysis (F<1, NS), suggesting that citalopram adminis-
tration had no effect on acquisition and short term recall.
108

Delayed recall

Mean performance in the delayed recall and recognition

component of the AVLT is given in Fig. 2. Recall
following the distracter [F(1,22)=6.6, P<0.05] and the 15-
min delay [F(1,22)=5.1, P<0.05] was significantly facil-
itated by citalopram administration. A facilitatory effect
of citalopram on long-term memory was also seen in the
recognition memory component of the AVLT
[F(1,22)=5.6, P<0.05].

Sustained attention

Fig. 1 Immediate recall over the five learning trials following There was no effect of citalopram on target sensitivity,
citalopram (black) or placebo (white). Values represent mean response bias or reaction time on this measure of
number correct€1 SEM
sustained attention (see Table 1).

Subjective ratings

The changes in memory occurred in the absence of any

subjective alterations in mood and anxiety, as judged by
standard visual analogue rating scales and the BFS scale
of mood changes (all comparisons, P>0.08).

Fig. 2 Delayed recall and recognition following citalopram (black
bars) or placebo (grey bars). Top graph: following distracter list
and 15-min delay. Values represent mean number of items recalled,
expressed as a percentage of each subjects’ final score on the
immediate recall component of the AVLT. Lower graph: recogni-
tion memory. Values represent signal detection score, A’ €1 SEM.
Asterisks represent statistical comparison of the two groups:
*P<0.05
Discussion
Acute administration of citalopram was found to facilitate
long-term recall and recognition of verbal material in the
absence of effect on immediate recall in healthy females.
These results are consistent with previous findings, which
suggest decreased memory consolidation following re-
duction of serotonin activity with tryptophan depletion in
healthy volunteers (Riedel et al 1999). These data
therefore indicate reciprocal effects of serotonin in long-
term memory processes in humans. Citalopram adminis-
tration did not affect sustained attention performance or
subjective ratings of mood and energy, suggesting that the
memory effects are unlikely to represent a non-specific
action.
Results from animal studies have revealed inconsistent
findings concerning the role of serotonin in learning and
memory. However, in humans, tryptophan depletion,
acting to decrease serotonin neurotransmission, has
deleterious effects on memory consolidation. Using a
slightly different procedure from the one used here,
administration of a tryptophan free mixture prior to
learning was found to impair delayed recall and recog-
nition at both 30 min and 18 h after list presentation,
whilst leaving short-term memory intact (Riedel et al.

Table 1 Mean performance Citalopram Placebo Significance

(with SD in brackets) in the
sustained attention task follow- Reaction time (ms) 588 (25) 638 (44) F=0.9, P=0.3
ing citalopram (10 mg, IV) or Sensitivity (a’) 0.57 (0.01) 0.56 (0.01) F=0.3, P=0.6
placebo Response bias (b’) 0.85 (0.06) 0.92 (0.03) F=1.1, P=0.3

1999). The present data directly mirror this pattern of
results: enhanced long-term, but not short-term, memory
performance following citalopram. The present results
therefore provide additional evidence for the role of
serotonin in memory, and further suggest that increasing
serotonin levels can lead to enhancements in memory
consolidation.
These findings may have implications for our under-
standing of the effects of SSRIs on memory processes in
depression. Depression is associated with impaired
memory performance, which is ameliorated after suc-
cessful pharmacological treatment (Keegan et al. 1991;
Bondareff et al. 2000). The present data suggest that
SSRIs are capable of facilitating memory performance,
independently from symptom improvement. The volun-
teers in the current study were free from current or
previous depression and reported no changes in mood
following citalopram administration. The impaired mem-
ory seen in depressed patients may, over time, contribute
to the feelings of inadequacy and low self-esteem
associated with this disorder. Hence, it is possible that
antidepressant drug treatment effects on memory form a
valuable process in the response to such treatment.
However, while the effects seen here were restricted to
delayed recall, depression is associated with more global
cognitive deficits including impaired immediate recall
and attention (Austin et al 1992; Brown et al 1994). It
remains to be assessed whether this acute SSRI admin-
istration would have more global effects in volunteers
with pre-existing deficits in memory performance. It
would also be useful to characterise the effects of these
agents on tests tapping into different memory components
or subdivisions, such as working memory, autobiograph-
ical and emotional memory.
Vigilance performance was not affected by citalopram
administration in the current study. Previous studies have
reported decreased vigilance performance following oral
treatment with SSRIs in tasks demanding more sustained
processes of attention than the task used here (such as the
45-min version of the Mackworth clock; Ramaekers et al.
1995; O’Hanlon et al 1998). However, the 7-min task
does show a characteristic vigilance decrement over
testing and has been shown to be sensitive to other
pharmacological manipulations such as clonidine (Coull
et al. 1995) and amphetamine (McTavish et al. 2001).
This short task was used as a control for the level of
sustained attention required by the memory task and the
absence of an effect with IV citalopram therefore suggests
that alterations in this ability cannot explain the improved
memory performance seen in the current sample.
In summary, the current results suggest that adminis-
tration of a serotonergic agent enhances long-term
memory, in the absence of changes in sustained attention
or mood. These effects therefore confirm the facilitatory
role of serotonin in memory consolidation, as previously
suggested by studies investigating the effects of decreased
serotonin function in humans.
109
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